Paliperidone, or 9-hydroxyrisperidone (chemically: (±)-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl)ethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one) of the formula (I):
is a major human metabolite of the known antipsychotic drug risperidone. It is marketed in tablets for oral administration under the brand name INVEGA™ (Janssen, L. P.) for treatment of schizophrenia. Paliperidone has one centre of optical activity (the carbon in the 9-position); both enantiomers are known but the marketed compound is a racemate.
Paliperidone (including enantiomeric forms thereof) has been disclosed in EP 368388 (U.S. Pat. No. 5,158,952). The same document discloses also esters of paliperidone with carboxylic acids having the formula (II) (R′═C1-19 alkyl).

A preferred ester compound (II) is paliperidone palmitate, which is currently under development for use in injectable compositions with prolonged action.
Various processes for making compounds of formula (I) and (II) have been generally disclosed in the EP 368388. One process is based on an alkylation of a 3-piperidinyl 1,2-benzisoxazole of the formula (2) with the compound of formula (1.1), wherein R is hydrogen or C1-C20 acyl group and A represents an appropriate leaving group such as, for example, halo, e.g., chloro, bromo or iodo; sulfonyloxy, e.g., methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, 4-methylbenzenesulfonyloxy and the like leaving groups.

Another known process is based on the reaction of the same compound (1.1) with an oxime compound (3), wherein L is a reactive leaving group, followed by the ring closure of the isoxazole ring on the intermediate (4):

Furthermore, the esters of formula (II) may be prepared by acylating paliperidone (I) by an acylation agent (e.g. acyl halide or acyl anhydride).
As apparent, the compounds of the general formula (1.1) are valuable intermediates in making paliperidone (I) as well as the paliperidone esters of the formula (II). A typical example of the intermediate of the general formula (1.1) is the compound 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one of the formula (1a)
A known process for making the compounds of general formula (1.1) is based on making the corresponding O-protected starting material, followed by a reductive deprotection. An example of such process for making (1a) is shown below in Scheme I (Bn is benzyl group).
The yield in such a process is generally low, e.g. 50%, and the compound (1a) is not readily obtained as a crystalline compound under the usual reaction conditions, which is also disadvantageous.
As paliperidone is a structurally very similar to the known antipsychotic drug risperidone, the synthesis of which being very well known and elaborated, it occurred to the present inventors that it would be convenient to use risperidone or its starting materials in the synthesis of paliperidone and its O-acyl analogues. For instance, the risperidone starting materials of formula (5.1), which lacks the 9-OH group of formula (1) that is needed in the final paliperidone, are commercially available (A=Cl) and can be produced in good yields.
But, no process for a conversion of the compound (5.1) (or its subsequent intermediates through risperidone) into the compound (1.1) (and the corresponding subsequent intermediates through paliperidone) has been disclosed in the art. Therefore, a discovery of such a process is desirable.